Quantitative prediction of human clearance guiding the development of raltegravir (MK-0518, Isentress) and related HIV integrase inhibitors. Drug Metab. Dispos

Human HIV integrase inhibitors are a novel class of antiretroviral drugs that act by blocking incorporation of the proviral DNA into the host cell genome, a crucial step in the life cycle of HIV. In the present work, quantitative methods for prediction of human phar-macokinetics were used to guide the selection of development candidates from a series of dihydroxypyrimidine and N-methylpyri-midinone carboxamide inhibitors of HIV integrase, which are cleared mainly by O-glucuronidation. The pharmacokinetics of 10 drugs from this series was determined in several preclinical spe-cies, including rats, dogs, rhesus monkeys, and rabbits, and the in vitro turnover, plasma protein binding, and blood/plasma partition ratio were studied using preparations from both preclinical species and humans. Two clearance prediction methods, based on physi-ologically based scaling or allometric scaling normalized for dif-ferences in microsomal turnover, were used to extrapolate huma